The goal of the proposed project is to develop a nonaddicting analgesic for chronic and acute pain. There is an urgent need for effective treatments for chronic, neuropathic pain, a relatively common complication of diabetes. As diabetic neuropathy progresses, neuropathic pain becomes increasingly difficult to treat with currently available analgesics such as anti-depressants and opioids. Morphine and its analogs are routinely prescribed, inspite of their side effects, because good analgesics are currently not available. Newly identified nociceptin and its analgesic activity in animal studies provide a potential target for the relief of chronic and neuropathic pain. Because the nociceptin antagonist does not act through opiate receptor, addiction and opioidrelated side effects may not be a problem. However, because of its size (17 amino acid) and peptidic nature, nociceptin is not going to make it as a therapeutic agent; a small non-peptide analog will be required to commercialize any compound. During Phase I studies, we were able to identify a group of small derivatized hex peptides with high binding affinity to human ORL I receptor. In addition, we were able to identify potent analogs with functional activity ranging from nearly a full agonist to a complete antagonist, at least 10 times more potent than the reported antagonist. Our antagonist-derivatized peptide has been shown to potentate morphine analgesia and possesses some analgesic activity on its own. Our derivatized haxapeptides have great potential as analgesics and the findings of Phase I will form the basis for the further development of a nonaddicting analgesic for chronic and acute pain. The specific aims for Phase II are: (I) Design non-peptide analogs of potent derivatized hex peptides to enhance potency, efficacy, and half-life. Conduct computational experiments to design these analogs. (ii) Conduct in vitro experiments to study binding affinity. (iii) Conduct functional assay on high affinity compounds to determine agonist and antagonist activity. (iv) Conduct in vivo experiments on high affinity agonists and antagonists for analgesic or nociceptive activity. (v) Conduct in vivo experiments on the most effective agonist and antagonist to determine their actions in chronic pain modes. The data generated by these studies will provide important information to bring this technology to a level of maturity where it can compete successfully for commercial funding to bring an effective therapeutic agent to clinical use. PROPOSED COMMERCIAL APPLICATION: Non-peptide analogs of nociceptin, prepared under this program, will be developed into therapeutics that can be used for the treatment of chronic and neuropathic pain. For this type of debilitating chronic injury, there is no suitable treatment available currently. Market opportunity for analgesics is worth in excess of $5 billion and is growing rapidly. The development of non-peptide agonists would likely add effective compounds for this enormous market.